Theiler's murine encephalomyelitis virus (TMEV) is an endemic murine pathogen that induces a demyelinating disease (TMEV-IDD) of the central nervous system (CNS) in susceptible mouse strains with accompanying CNS histopathology characterized by mononuclear cell infiltrates. TMEV-induced demyelinating disease is initiated by CD4+ T cell immune responses to viral proteins early in disease and self proteins in later disease. In susceptible strains of mice such as SJL, TMEV establishes a persistent infection in macrophages, induces a CNS infiltration of macrophages, T cells, and B cells, which results in chronic progressive paralysis. The chronic paralytic nature of the TMEV-induced clinical disease course as well as the CNS pathology presents as a very good model for the human CNS demyelinating disease, multiple sclerosis (MS). One of the major goals of this proposal is to define the cellular and molecular mechanisms that regulate the immunopathogenesis of this chronic inflammatory CNS demyelinating disease. Mononuclear cells infiltrate tissue sites during inflammatory processes and a family of chemotactic cytokines called chemokines have been implicated in this gradient-induced cell migration. The central hypothesis of this proposal is that chemokines are expressed in the CNS during TMEV-IDD and regulate immune responses including cell migration patterns that are required for demyelinating disease development and progression. This hypothesis will be tested by examining the following specific aims: 1) determination of the mechanisms of chemokine function in the initiation of TMEV-IDD 2) determination of the mechanisms of chemokine function in the progression of TMEV-IDD; and 3) determination of chemokine receptor expression and function in the development of TMEV-IDD. These studies will help to understand the immunopathogenesis of MS and provide a basis for the development of novel therapies designed at targeting molecules involved in the migration and accumulation of pathogenic lymphocytes and monocytes into the CNS during the induction and progression of inflammatory demyelinating diseases.